About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

December 14, 2006

Love and Anger

Posted by Derek

Glenn Reynolds gave the pharma industry a much-appreciated thank-you card over at Instapundit:

Only a moron would want to live in a society where people are ashamed to work for drug companies. And yet, I'm not surprised to see that resulting from the demagogy that abounds among politicians and "public interest" types who are not serving the public interest whatsoever.

I'm thinking of having that first sentence engraved on something expensive. Glenn's post prompted Dean Esmay to write a short post on the ethics of drug companies, though, and he's rather less positive. I suppose I shouldn't be surprised, given some of the things he's gone in for in the past. As usual, some of the problem is the difficulty that people have coming to terms with the fact that drug discovery is a for-profit industry.

Drug discovery used to be a total crap-shoot but it's getting more and more targeted as the years go by thanks to ever more sophisticated computer modeling. They are now able to say "okay, this is the chemical receptor that we think we need to address, let's design a molecule that fits into it." This is essentially a nanotechnology, although not the type most people think of when they hear the term.

Ay, would that it were true. As my industry readers know, and as I've been ranting abouit here fairly often, drug discovery is just as much of a crap-shoot as it's ever been. And wouldn't it be great if "sophisticated computer modeling" helped that much? Instead, we get things like this. No, I think what's happening here is that we're being underestimated by our enemies and overestimated by our friends. . .

What's strange is that in the piece by Reynolds you link to, Derek, it is obvious that the ones that think it's a shame to work for Pharma are some people actually working for Pharma... the person ashamed was a Director at Pfizer talking to her nephew!

Unfortunately there's always this conflation of criticism of Pharma with science-phobic lunatics, and I think sometimes you go into that comfortable territory, Derek. The best criticism of Pharma comes from people that are directly related to science, but using some easy and twisted extrapolation argument, pharma cheerleaders end up dismissing serious critics simply because the lunatic fringe also criticizes Pharma, pretending they are the same.
But I do agree with your last paragraph, Derek. I do think that critics often underplay Pharma's place in the common good, and cheerleaders often overplay its wonders.

I was born in country ruled by commies and lived there until their sorry end - and would you believe they were saying exactly the same apologetic crap about teachings of Marx and Lenin, how the ideas and the system were great and would have worked wonderfuly if people were better.

People in med chem should be constantly reminded that docking is a poor substitute for a crystal structure data and should be used only as one way of making educated guess among many others.

In my opinion people that do computer modeling often have only shallow understanding of medicinal chemistry process and too much self-promotion and wishful thinking has dominated the field in the past. Also business folk in management tend to love this kind of crap because they think computer modeilng can iluminate things and take serendipity out of the discovery. To me it is just a form of witchcraft done in front of the monitor.

The problem with computer modeling again, is that people either underestimate or overestimate it. It is very important to understand the context and limitations, and confidence levels of your predictions and analyses. You cannot look at the top pose from a docking result and say it is the correct one. However, if that top pose shows up in the top twenty hits about twelve times, for different levels of docking accuracy, then the significance of that pose becomes more interesting.
In any case, as far as prediction is concerned, even experimental approaches are often no better. For example, there is no way to predict in a foolproof way, either computationally or experimentally, whether there will be an extra pocket that opens up in a protein that will have an allosteric interaction with a drug. This can only be discovered after the experiment is done. What experimental approaches are really good at is giving you the picture, which if obtained honestly and as rigorously as you can, may be closer to the 'truth' than anything else. But even then there can be a lot of elements that can distort the results.
Any while it's true that many modelers have a hazy understanding of med chem, many experimentalists also have a hazy understanding of what it is that modeling can supply us with. In addition, many don't think rigorously enough about conformation in general, and end up proposing a single conformation for a flexible molecule in solution by NMR.
I believe that one of the greatest benefits of good and reasonable computational chemisty training is that you get a feel for what it means to have a 2kcal/mol difference in binding energies, what it means to evaluate a single conformation from NMR, and other such things, which someone who is doing physical organic chemistry also thinks of for example.
And there are many computational chemists out there who are well aware of the limitations of their paradigm; Jorgensen, Houk, and the late Peter Kollman to name a few.

And by the way, I don't think the comparison with communism is apt. Communism in my opinion is an inherently flawed system (although it may not seem that way). I would never like to live even in a perfect communist society, even where the principles are orchestrated spotlessly by the people in charge. So in case of communism, apogetic behavior is indeed a cover up for the innate flaws of the system. Computer modeling is not an inherently flawed field, just one that must be used with cerebral caution.

As a semi-adjacent person to this fray, my problem with the current for-profit pharma is that it is inefficient. We (consumers, taxpayers, etc) subsidize a massive amount of inefficiency through patents and high drug prices in order to "promote progress", i.e. to push innovation beyond what the free market values it at. The problem with this is that I just don't feel we get all that much bang for the buck. This isn't pharma's fault per se, it is an issue of the basic science not being there yet. I just don't think torcetrapib was worth 20 billion dollars or whatever the drug sales would have been to recoup the R&D had it not flopped.

The day will come when the science progresses to the point that drugs can be semi-reliably designed. Then drug development costs will be reasonable and innovation useful. Until then we're just wasting countless amounts money on thousands of pointless screens and combinatorial libraries in the hope of finding the one in a million.

"As usual, some of the problem is the difficulty that people have coming to terms with the fact that drug discovery is a for-profit industry."

Perhaps the point is that maybe pharma shouldn't be all for-profit.

I know this is a tired complaint, but you seem to have difficulty coming to grips with the fact that people are going to feel some moral indignation at drug companies focussing resources on treatments for lifestyle problems (impotence, nail fungus, etc.) rather than life-threatening diseases on the basis of profit potential. This is, of course, the nature of a for-profit corporation, but like many other such decisions that companies in many industries make to trade lives for profit, it leaves a bad taste.

It's foolish to deny that the products of the pharmaceutical industry have had an enormous positive impact on the lives of people around the world. However, it's also pretty puzzling to think that there aren't some entirely valid concerns about the behavior of pharma companies and the setup of the entire system.

Look, you can be a perfectly rational, pro-capitalism economist and still not be impressed by the drug companies.

Essentially the US is currently funding world R and D on drugs while letting the rest of the world buy close to marginal cost while we pay much more. There is perfectly good reason to resent this state of affairs, and that would be even if the drug companies weren't entirely complicit in this situation arising. Further, your industry spends tens of millions of dollars (or more) on your lobbyists in Washington and have conspired to get legislation amazingly hostile to the american interest passed (viz the current drug-company welfare act / Medicare part D).

I would humbly suggest that your industry could improve its public perception if they stopped buying off Congress. Part two would be to acknowledge that America overpays for drugs. Letting America negotiate best-price purchasing agreements is completely reasonable. This would probably force drug companies to raise their prices for the rest of the developed world but frankly that isn't my problem. It's time for the EU, Canada, Japan, and S Korea to start paying their share of the R and D costs.

That being said, your industry does do a lot of good in the world, and the development of drugs makes the world a better place. I understand that it is a difficult task and very expensive, and there are an array of people who work very hard to create new drugs that enhance or save peoples' lives. I think virtually no one in your industry intentionally harms consumers and that the bad outcomes that have occurred are mostly due to a poor understanding of the human body and the inevitable tradeoffs that occur any time you put a chemical in your body.

However, you must be wearing some serious rose-colored glasses to not understand why a good chunk of America isn't enthralled with your industry. Particularly since people like me aren't the rabid anti-industry types many industry advocates would prefer to write us off as.

The central question here is, do drugs really need to be all that expensive? Is all that money from sales really necessary to pay off patent, development, and clinical trial expenses? Actually I don't think it is. The question is about profit margins. And there we tread into the old familiar thorny dilemma; how much profit is enough profit? And if the criticism is about making shameless profits off drugs, then why target only pharma? Many corporations under capitalism do that.
So I think that the whole issue of drugs being expensive is simply related to the whole issue of whether we can actually criticise excessive profit making.

As someone who has worked in the biotech and medical device worlds I have to reply to WonderDrug. Do drugs (or devices) need to be so expensive?

Mostly. Development is very expensive, because so few products make it to market. The vast, vast majority of drugs don't make it to market. The few that do have to pay for everything - in around 10 years. A third to a half of a patent's life goes by before a drug or device even gets to market. The other risk is that once approved, a drug can be taken off the market by regulatory agencies, sometimes without much (or any) warning. Nobody has ever ordered Ford to stop selling cars because a small, but statistically significant number of people died while driving them, but the FDA has ordered numerous drug companies to take drugs off the market for this - a problem that may not become apparent until tens of thousands of people have taken the drug.

Lovastin- OTC drugs fall under the exact same regs for development and manufacturing as prescription drugs, plus extra regulatory reviews to insure that the drug is safe enough (for example, few drug interactions) for a consumer to use without medical supervision.

But I would think that with so much development behind them, the processes and manufacturing of drugs like ibuprofen and aspirin would have become standardized, and would not need as much scrutiny as, say a cardiovascular disease drug. In spite of this, even OTC drugs are much more cheap in other countries, and just as reliable. Or are there actually statistics that show that standard aspirin taken in say India or China is much more risky than standard aspirin taken in the US? If not, why does even aspirin need to be expensive in the US? I can probably understand the high prices of new or revolutionary drugs, but why aspirin?

I'm not sure where you are coming from. Generic aspirin is dirt cheap; most OTC drugs are pretty cheap. And even if you are mad about the cost of OTC drugs, what does that have to do with drug discovery or Big Pharma? Blame the OTC companies . .

I think Palo has it about right. We need to address the very real concerns facing the pharmaceutical industry, and not just defend everything. Commercials for erectile dysfunction drugs are not in the best interest of anybody. Bribing doctors to prescribe certain drugs is bad. Pushing through dangerous drugs is bad (CAVEAT: I may have a very different definition of the word "dangerous" than you, and we need to recognize this).

That said, much of the criticism I see in this thread is unfounded. To whit:

Current patent law makes drugs more expensive. "Huh?", you say. Well, if I had 20 years of exclusivity instead of 6, I could charge a lot (a LOT) less, and still make a reasonable profit.

What is a reasonable profit? I don't know, ask the markets. And right now, the markets are saying that pharmaceutical companies are not making ENOUGH profits, as should be clear by viewing a five-year chart of every Big Pharma out there.

The day will come when drugs can be developed less expensively? Oh, I certainly hope so. But your solution until that magical day is stop trying? How, prey tell, do we get there if we stop trying?

Yes, we have real problems. But so many of the arguments against the industry are unfounded that it becomes tiresome to sort out which are which. But we should certainly make the effort.

On the Lilly Icos thing. If those ICOS investors are so sad that there won't be any more jobs after Lilly buys them (one of the founders said that he was disappointed), why don't they just take some of that 2+ billion and start another company and hire a few of those newly out of work people. 2+ billion ain't bad startup money. Lilly only wanted Cialis and my guess is that buying the company is the only way they could get it. The greedy people are the ones cashing out. Lilly just made a business decision.

I have read the above discussion; what is said about the extremely high cost of developing a drug is justified. One only wished that with such a top notch drug development system, the US also had the best health care in the world. Does it though?

One only wished that with such a top notch drug development system, the US also had the best health care in the world. Does it though?

Depends how you want to measure it.

Longevity? (Answer = no)

Access to treatments of choice? (Answer = probably yes, even for those without insurance)

Infant mortality? (Answer = perhaps not, but how much is it a function of the health care system vs a function of population genetics / demographics, etc.)

Time to treatment (Answer = probably yes)

Per capita spending (Answer = if a number is all you're after, no, but if a value is placed on things like freedom of choice, personal preferences, etc., perhaps a focus on cost alone is misleading.)

In other words, it's no great challenge to point at one statistic or another to support a particular viewpoint about whether one system is the "best" or not, but it's quite a bit more challenging to look at the whole system to reach a judgment which considers biology, economics, culture, personal autonomy, etc.

@Palo: "What's strange is that in the piece by Reynolds you link to, Derek, it is obvious that the ones that think it's a shame to work for Pharma are some people actually working for Pharma... the person ashamed was a Director at Pfizer talking to her nephew!"

I suspect that's a total misreading of the comment. I would bet that the Director at Pfizer is actually very proud of her work and her industry, but she probably has found it easier just to apologize to people than it is to engage in yet another unwinnable argument (particularly in what should be a fun, social setting) with people who are inclined to think that the industry is sitting on a cure for cancer (since, of course, cures destroy the marketplace for drugs, right?), etc.

I don't understand why everyone should try to justify anything about pharma (or big corporations in general) in blanket statements. Me, I just look at it as a necessary evil (just like democracy ;). And I think Mac's question was more rhetorical :-)
Also, I don't see anyone saying anything about Earl's comments, which seem justified to a large extent.

@Steakandale: I don't see anyone saying anything about Earl's comments, which seem justified to a large extent.

No, it's just tiresome to keep responding to variations on an old theme. For example:

Earl: I would humbly suggest that your industry could improve its public perception if they stopped buying off Congress.

Sure. The industry would be much better off letting the groups which tend to think that the industry is evil or which favor socialized medicine to do the buying off by themselves. That way, the industry can feel good about itself as it is legislated out of existence.

Earl: Part two would be to acknowledge that America overpays for drugs.

By what criteria? Perhaps one might just as easily acknowledge that other nations underpay for drugs. What would the long term impact of reducing prices to much lower levels be? Of course, many insist that there would be little effect on R&D (since the industry could always cut marketing instead) or that the government would just keep on discovering new drugs instead. Maybe I'll get a pony for Christmas, too.

One sided assertions might feel good, and might show that one "cares", but that doesn't make them right.

"By what criteria? Perhaps one might just as easily acknowledge that other nations underpay for drugs."

I don't think such a question honestly tackles the problem. One might as well say, "By what criteria are African countries poor? Perhaps it's just that other countries are simply too rich".

My point is that one has to give at least some value to relative comparisons with other countries. If we don't do that, then publishing a World Development Index every year would be futile. The fact is that drugs in the US are expensive compared to drugs in other developed countries, and this fact is not necessarily reflecting in factors like longevity or child mortality.
I don't want to comment on whether this is "fair" or "good", but I don't think we can simply turn a blind eye to this.

I think all those who criticize the industry for profit making are as usual barking up the wrong tree. It is important to criticize those things that really matter- like all the under-the-table perks and incentives that are given to doctors by companies to pedal their drugs.

Jerry Kindall doesn't know what he's talking about. And milkshake, sounds like you've had some rather poor interactions with modelers, or just had the misfortune to work with bad ones.

Sadly academics does not train molecular modelers properly, as the types of things you do in academia are almost never done in industry (i.e. MD/MC, lots of ab initio stuff, reaction mechanism, FEP, etc.)

Donm Luskin has a quote from Adam Smith on apothacaries. Kind of looks like we are trying to learn something Ol' Adam understood clearly over two hundred years ago: The price of a drug has all the costs associated with its development and manufacture.

"Apothecaries' profit is become a bye-word, denoting something uncommonly extravagant. This great apparent profit, however, is frequently no more than the reasonable wages of labour. The skill of an apothecary is a much nicer and more delicate matter than that of any artificer whatever; and the trust which is reposed in him is of much greater importance. He is the physician of the poor in all cases, and of the rich when the distress or danger is not very great. His reward, therefore, ought to be suitable to his skill and his trust; and it arises generally from the price at which he sells his drugs. But the whole drugs which the best employed apothecary in a large market-town, will sell in a year, may not perhaps cost him above thirty or forty pounds. Though he should sell them, therefore, for three or four hundred, or at a thousand per cent. profit, this may frequently be no more than the reasonable wages of his labour, charged, in the only way in which he can charge them, upon the price of his drugs. The greater part of the apparent profit is real wages disguised in the garb of profit."

You would be surprised - my ex-boss is a protein molecular modeler by background and original career, we were pretty close and I we discussed what to make/not to make based on protein structure quite frequently and I think he was pretty good. He had very sceptical take on value of lots of stuff that passes for docking - when it is not supported by a closely-related X-ray co-crystal data.
(My another ex-boss and a very good friend was doing fairly high-level transition state ab inition calculations; he was working on it with Houk).

My chierf complaint is that molecular modeling for pharma research is hugely overhyped and many people that try to develop docking software packages for pharma industry do not bother to find out how useful their craft realy is. The test of any docking software should be to take X-ray structure of protein, take a known tight inhibitor and have somebody naive (about this particula protein and inhibitor) to dock the inhibitor in. The result should be then compared with the actual solved X-ray co-crystals. When you do it for 20 dissimilar proteins and 40 inhibitors (these should be different from ones from those used to calibrate the software) - and after you can get 40% success rate I will gladly admit your software is useful.

I don't know if this is of interest, but there is a posting on Slashdot about patents and pharmaceuticals. The site tends to be relatively anti-patent, but it might represent the opinions of at least some people on patents, pharmaceutical companies, and drug costs.

Dana H., how far can you take the logic? Would you be ok with companies pricing anything any way they want? Would you be ok if the companies just shrug it off always and tell you, "You always have the right to not buy our product".
Tomorrow, they will raise the price of drinking water a hundred fold and say "Don't buy our water; you will be no worse off drinking only 3 glasses instead of 7 glasses a day". Would you be ok with that, with not being able to drink water to your satisfaction and whim? After all, staying a little thirsty is not much worse than enduring a bad headache, isn't it?
This is just shifting the blame on to the consumer. That does not solve the problem.